Canagliflozin (Invokana™) vs. Standard Dual Therapy Regimen for T2DM During Ramadan

There are over one billion Muslims in the world with the majority participating in Ramadan. The prevalence of diabetes in several countries with large Muslim populations is similar to the rates observed in westernised countries, which increases by 10% annually as a result of urbanization and socioeconomic development. Observance of Ramadan is an integral part of Islamic identity being one of the five main pillars that constitute this widely followed religion. Muslims observing Ramadan are required to fast from sunrise to sunset during this holy month. The timing of Ramadan follows the lunar calendar which occurs 10 days earlier each year; this means that the fasting period coincides with the summer season for many consecutive years before moving in line with the winter months. During the summer season Ramadan can take place with the longest hours of daylight which has a greater impact and risk for people with diabetes who fast during this period.

Although the Quran exempts "sick" people from the duty of fasting many Muslims with diabetes do not consider themselves to be sick and are keen to fast. A recent epidemiological study involving 13 Islamic countries reported that 43% of patients with Type 1 diabetes mellitus (T1DM) and 79% of people with type 2 diabetes mellitus (T2DM) fast during this religious period.

Concern for Muslims with diabetes fasting during Ramadan has been recognised by religious leaders and indeed 2009 saw a landmark event. A statement was issued at the meeting of the Council of the International Islamic Fiqh Academy of the Organisation of Islamic Conference at its 19th session. In brief, people with diabetes were classified into four categories in line with expert recommendations published in 2005. Categories 1 and 2 include those with diabetes at very high risk of serious complications and high risk of complications due to fasting, respectively. These two groups are exempt from observing Ramadan. Categories 3 and 4 include those with diabetes who have a medium risk of complications and those with a low risk of complications due to fasting, respectively. The latter two groups are not automatically exempt from observing Ramadan. The risk of complications in this context refers specifically to the likelihood of hypoglycaemic events, and includes other acute illnesses associated with diabetes, patients on renal dialysis, women with diabetes during pregnancy, patients with macrovascular disease, and those who live alone and are on insulin therapy or oral insulin secretagogues. Additionally, all people with T1DM are classed as category 1. However, the impact of the feasting part of Ramadan, for example on hyperglycaemia or deterioration of glycaemic control, is not considered in this statement. Furthermore, it is not known to what extent these guidelines are followed in practice.

There is an abundance of evidence describing the impact of Ramadan on people with T2DM from retrospective to population-based studies. However, there is a lack of evidence available to help guide the management of people with diabetes who wish to observe Ramadan. Fasting and feasting during this holy month can cause health risks for people with diabetes. The Epidemiology of Diabetes and Ramadan 1422/2001 Study ("EPIDAR") was a large population-based, international epidemiological study of diabetes conducted in 13 countries with Muslim populations. One of the aims of this study was to determine the potential effects of fasting in people with diabetes on their well-being and the management of this condition. They observed a 7.5-fold (from 0.4 to 3 events per 100 per month) increased risk of severe hypoglycaemia in patients with T2DM as a result of a change in eating patterns during Ramadan. Severe hypoglycaemia was defined as hypoglycaemia leading to hospitalization. Additionally a 5-fold increase in the incidence of severe hyperglycaemia with/without ketoacidosis was observed in patients with T2DM.

Other risks for people with diabetes who fast during Ramadan include diabetic ketoacidosis due to a lack of insulin, dehydration due to lack of fluid intake during the fasting period, and orthostatic hypotension in addition to an increased risk of thrombosis due to increased blood viscosity secondary to dehydration. Only 62% of those with T2DM in the "EIPDAR" study reported receiving recommendations from their health care providers. These recommendations should include changes in lifestyle (diet and physical activity) and in medication choice and dosage to limit the potential complications of fasting and feasting for this patient population.

There have been significant advances in glucose lowering therapies in T2DM and their availability, thus offering a greater choice of therapies to people with diabetes with the potential for supporting safer fasting. Three new classes of therapy have been licensed for the treatment of T2DM in the United Kingdom (UK) in the past 10 years. The most recent class that has been introduced are the Sodium Glucose Co-Transporter 2 Inhibitors (SGLT2 inhibitors). There are six known members of the SGLT family to date. Canagliflozin (Invokana™), a once daily tablet, is one of a number of SGLT2 inhibitors that have been licensed within the UK. This medication is taken once daily orally (either 100 or 300mg). Phase III trials of this novel agent have reported reductions in HbA1c between 0.70 and 1.16%, body weight reduction between 1.8 and 3.7% and systolic blood pressure reduction between 1.6 and 6.6mmHg (millimetre of mercury) from baseline. Canagliflozin (Invokana™) has a low intrinsic propensity to cause hypoglycaemia. Importantly this drug is reported to be well-tolerated and has a good safety profile in patients with inadequately controlled T2DM as monotherapy or in combination with other glucose lowering therapy including sulphonylureas and metformin.

In 2016, Ramadan takes place throughout the months of June and July. At this time of year in the UK, between dawn and sunset there are approximately 14.5 hours of daylight at the beginning and 13 hours towards the end of Ramadan during which there is fasting. This is a significant portion of the 24 hour day; thus abstinence from food for such a prolonged period poses an increased risk for those with T2DM especially if their medicine regimens are not altered to accommodate this. In light of this the study aims to determine if the addition of Canagliflozin (Invokana™) therapy to monotherapy of metformin is more effective at achieving the double composite endpoint of a reduction in HbA1c (≥ 0.3%) and weight loss (≥1kg) 3-4 weeks post-Ramadan. The study will also include patients currently on dual therapy, specifically metformin plus a sulphonylurea, pioglitazone or repaglinide to determine whether switching to metformin plus Canagliflozin (Invokana™) is more effective at achieving the composite endpoint compared to those remaining on previous dual therapy. There are a number of secondary outcomes including weight loss, rates of hypoglycaemia, blood pressure and a number of biochemical endpoints.

The study will also include an objective measure of glycaemic status using a Flash Glucose Monitoring System (FGMS) called a "FreeStyle Libre" sensor in a sub-set of participants (15-20 participants). Participants can 'opt-in' to the FGMS sub-study and the device will be worn before medication is initiated and at the first follow-up visit 3-4 weeks post Ramadan. The study will also invite those participating in the sub-study to wear the device during Ramadan. The use of FGMS will provide up to 14 days of blood glucose readings taken every 15 minutes allowing us to apply glycaemic thresholds to the uploaded data and calculate the proportion of time spent in hypo, hyper or normoglycaemic states in the two treatment groups.

There is limited evidence on the changes in levels of physical activity for people who observe Ramadan. It is widely believed that levels of physical activity are reduced due to a fear of feeling too weak [29]. To address this, the study will objectively measure physical activity levels before, during and after Ramadan in a sub-set of participants (15-20 participants) in addition to using the self-reported validated international physical activity questionnaire (IPAQ).

It is hypothesised that therapy based on Canagliflozin (Invokana™) is more effective than sulphonylurea-based regimen at helping people with established T2DM who are observing Ramadan to achieve the double composite endpoint of a reduction in HbA1c (≥ 0.3%) and weight loss (≥1kg) 3-4 weeks post-Ramadan.

STUDY DESIGN

This is an open label randomised controlled trial with two cohorts:

1. Cohort 1 - Individuals on metformin monotherapy will be randomised (1:1) to either the addition of Canagliflozin (Invokana™) or repaglinide, a sulphonylurea or pioglitazone, and
2. Cohort 2 - Individuals on dual therapy (metformin plus repaglinide, a sulphonylurea or pioglitazone) will be randomised (1:1) to either continuation of their current therapy or to switch to metformin and Canagliflozin (Invokana™) Randomisation will be stratified by site and entry therapy (monotherapy OR dual therapy which includes metformin plus pioglitazone, or metformin plus either a sulphonylurea or repaglinide, respectively) resulting in 6 stratification groups. Randomisation will not be carried out until after the baseline data have been collected.

The intervention group in Cohort 1 will be those randomised to metformin + Canagliflozin (Invokana™). The control group in Cohort 1 will be those randomised to receive metformin plus repaglinide, or a sulphonylurea or pioglitazone in line with current National Institute for Health and Care Excellence (NICE) guidance as the preferred second-line therapy after metformin.

The intervention group in Cohort 2 will be those randomised to switch to metformin plus Canagliflozin (Invokana™). The control group in Cohort 2 will be those who continue with their current medication.

The study will recruit patients from both primary and secondary care in Leicester and Birmingham. It is envisaged to commence recruitment in February 2016, although this date is conditional upon on ethics committee and regulatory approval and necessary preparatory arrangements, including research governance approval at both sites. Actively recruitment will begin once all approvals are in place and after Sponsor 'green light' has been issued.

Randomisation and Code breaking:- There will be six randomisation lists. Participant identifier numbers will be assigned sequentially as each subject enters the study. The participant will be assigned a study drug through a randomisation schedule based on the randomisation plan.

Randomisation will be stratified by site and entry therapy (monotherapy OR dual therapy which includes metformin plus pioglitazone or metformin plus either a sulphonylurea or repaglinide) resulting in 6 groups using a variable block size of between 4 and 6. Participants will be randomised 1:1 to metformin + Canagliflozin (Invokana™) or to metformin + a sulphonylurea, or continuation of their sulphonylurea, repaglinide or pioglitazone.

Discontinuation/Withdrawal of Participants from Study Treatment:- Each participant has the right to withdraw from the study at any time without giving a reason and without any future care being affected. The investigator may discontinue a participant from the study at any time if the investigator considers it necessary for any reason. The reason for withdrawal will be recorded in the case report form (CRF) and documented in the medical notes. If the participant is withdrawn due to an adverse event, the Investigator will arrange for follow-up visits or telephone calls until the adverse event has resolved, stabilised or concluded.

Source Data:- Source documents are original documents, data, and records from which participants' CRF data are obtained. These include, but are not limited to, hospital records (from which medical history and previous and concurrent medication may be summarised into the CRF), clinical and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. CRF entries will be considered source data if the CRF is the site of the original recording (e.g., there is no other written or electronic record of data). Specifically, for this study the CRF will be used as the source document for all anthropometrics, questionnaire and biochemistry that is collected during the study visits and copy of the biochemistry and anthropometric results will be put into the patient medical notes.

Drug Management Storage of Study Treatment:- The local National Health Service (NHS) Trust pharmacies will supply the licensed products and will handle it according to their in-house protocols. The study will be conducted in accordance with the Helsinki declaration. All staff working on this study will have an up to date International Council for Harmonisation -Good Clinical Practice (ICH-GCP) certificate.

Compliance with Study Treatment:- The study will measure compliance by requesting participants to bring all unused or part-used medications and packaging from used medication at each visit. This will be recorded in the drug accountability log as part of the CRF. A participant who ceases to take their medication for up to two weeks will be considered 'non-compliant'. They will have the opportunity to re-initiate medication.

Accountability of the Study Treatment:- The local NHS Trust pharmacies will dispense the study medication from their own stocks and they will also provide the appropriate drug labels. Returned and unused medication will be recorded by the research team and the research team will provide pharmacy with this medication at the end of the visit so that they can be destroyed in accordance with local regulations. Metformin will be prescribed as per usual by their General Practitioner (GP).

Concomitant Medication:- Throughout the study, Investigators may prescribe any concomitant medications or treatments deemed necessary to provide adequate supportive care except for those listed in the exclusion criteria. If the participant is subsequently prescribed excluded medication they will be withdrawn from the study.

SAFETY REPORTING Please note the Sponsor of the Study (University of Leicester) and the Chief Investigator shall be responsible for complying with UK Competent Authority (Medicines and Healthcare products Regulatory Agency (MHRA)) safety reporting requirements and be responsible for the participating (co- or sub-) investigators, as defined in the applicable laws and regulations.

As provided for in Article 3 of the Research Funding Agreement, the Sponsor and Chief Investigator will submit the safety information requested on the 'Clinical Serious Adverse Event Report' form (FRM-09210, Version 9.0) to the identified Janssen Pharmaceuticals Inc. representative of the country of origin, (i.e., Drug Safety Department of Janssen-Cilag Ltd) either by fax 01494 567799, or secure email and pdf to "Dsafety@its.jnj.com". For additional support, the Janssen-Cilag Ltd Drug Safety Department can be contacted on 01494 567 447.

Reporting Procedures for All Adverse Events (AEs):- All AEs occurring during the study observed by the investigator or reported by the participant, whether or not attributed to study medication, will be recorded on the CRF. The following information will be recorded, description, date of onset and end date, severity, assessment of relatedness to study medication, other suspect drug or device and action taken. Follow-up information will be provided as necessary.

Reporting Procedures for Serious Adverse Events (SAEs):- All SAEs must be reported to the Sponsor within one working day of discovery or notification of the event. The Sponsor will perform an initial check of the information and ensure that it is reviewed at the next R\&D Management meeting. All SAE information must be recorded on an SAE form and sent to the Sponsor. Additional information received for a case (follow-up or corrections to the original case) needs to be detailed on a new SAE form and sent to the Sponsor.

The Sponsor will report all Suspected Unexpected Serious Adverse Reactions (SUSARs) to the MHRA and the Research Ethics Committee (REC) concerned. Fatal or life-threatening SUSARs must be reported within 7 days and all other SUSARs within 15 days. The Chief Investigator will inform all investigators concerned of relevant information about SUSARs that could adversely affect the safety of participants. The Sponsor will use the Summary of Product Characteristics (SMPC) as the Reference Safety Information (RSI) when determining the expectedness of any untoward medical occurrences and thus SAE/SUSAR reporting.

In addition to the expedited reporting above, the Chief Investigator will submit once a year throughout the clinical study or on request a Development Safety Update Report (DSUR) to the MHRA and REC.

STATISTICS Description of Statistical Methods:- Participants recruited to the study will be compared by randomised group with respect to both their baseline characteristics and their pre-Ramadan characteristics. Numbers (with percentages) for binary and categorical variables and means (and standard deviations), or medians (with lower and upper quartiles) for continuous variables will be presented. There will be no tests of statistical significance nor confidence intervals for differences between randomised groups on any baseline variable.

The primary outcome of this study is the achievement of the double composite endpoint of a reduction in HbA1c (≥ 0.3%) and weight loss (≥1kg) 3-4 weeks post-Ramadan.

All analyses of outcome data will be carried out on a complete case basis according to randomised group. As a sensitivity analysis, for the primary and main secondary outcome, multiple imputations will be used to perform an intention to treat analysis. The investigator will also conduct a per protocol analysis excluding those who report no longer taking their randomised treatment at the two follow-ups. All analyses will be performed assessing change during the following time periods:

• Baseline to 3-4 post-Ramadan data constituting the primary analysis
• Pre-Ramadan to 3-4 weeks post-Ramadan ±2 weeks
• Baseline to 12 weeks post-Ramadan ±2 weeks
• Baseline to 12 months post-baseline ±6 weeks The primary outcome will be analysed using logistic regression adjusted for the stratification factors (site, entry therapy ((1) monotherapy (2) dual therapy metformin plus pioglitazone (3) dual therapy metformin plus either a sulphonylurea or repaglinide)). The dependent variable will be defined as those achieving all of the composite end point targets. The same analysis method will be used for the secondary composite outcomes.

The biomedical outcomes will be analysed using linear regression adjusted for the stratification factors and baseline value. Ordinal regression will be used to compare treatment groups for the treatment satisfaction scores. Linear regression will be used for total metabolic equivalent (total METs).

The percentage of patients experiencing one or more self-reported hypoglycaemic events in their diaries (defined as a blood glucose level of ≤3.9 mmol/l) will be reported by group along with the median (Inter Quartile Range) number of episodes per patient. The incidence rate of hypoglycaemia per person year will be calculated per group and compared using the incidence rate ratio (IRR).

Continuous Glucose Monitoring System (CGMS) data will be collected at 3 time points. The mean proportion (%) of time spent either above (≥10mmol/l), below (≤3.1mmol/l) or within (3.2-9.9mmol/l) - which are our predefined glycaemic ranges - will be calculated for each participant over the recording period and adjusted for 24 hours. The study will compare these by treatment group for each time-point. The investigator will calculate change in proportion of time spent in each category from pre-Ramadan against during and against post-Ramadan within each group. The investigator will then compare any identified glycaemic shifts between treatment groups. The investigator will calculate the number of Continuous Glucose Monitor (CGM) low glucose events (≤3.1 and ≤2.2mmol/L) and CGM high glucose events (≥10.0mmol/L) within each treatment group and determine if the incidence changes across the three time points.

The Number of Participants:- The sample size required to detect a minimum clinical significant difference of 27.7% in those achieving the primary outcome between the treatment arms is 116 participants (n=58 per group), with 80% power and an alpha of 5%, assuming a dropout rate of 20%. This is based on 21.2% of the SU plus metformin group in the 'Treat 4 Ramadan study' having met the proposed primary outcome of achieving the double composite endpoint of a reduction in HbA1c (≥0.3%) and weight loss (≥ 1kg) 3-4 weeks post-Ramadan.

The Level of Statistical Significance:- All analyses will be carried out in Stata (version 12.0) 95% confidence intervals will be reported with p<0.05 relating to statistical significance.

Procedure for Accounting for Missing, Unused, and Spurious Data:- Data will be entered into a database with real-time validation, which will limit spurious data. Before analysis begins all data will be checked and any anomalies will be checked against the source data.

During data collection the study team will attempt to minimise missing data items. Participants with missing data will be excluded on a case-wise basis, i.e., only from those analyses which required the missing items. The primary and main secondary outcomes will be analysed on both a complete case basis and using multiple imputation to estimate the effect of missing data.

QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES A monitoring plan will be developed by the Sponsor in accordance with Sponsor Standard Operating Procedures (SOPs). The monitoring plan will be based on a study risk assessment which is determined by the level of risk within the study to participant safety and data integrity and validity; monitoring will be carried out by monitoring staff employed by the Sponsor.

The Leicester Diabetes Centre in conjunction with the Leicester Clinical Trials Unit will be responsible for all elements of study management on an ongoing basis. For example, the CRFs will be checked for completeness at the end of a measurement session and any data queries will be raised with the research nurse who recorded the data in the first instance. Repeated errors will be referred to the Senior Research Team Manager who will instigate training. The study monitor will remain external to the study team thereby ensuring independence during the sponsor monitoring process. All in-house monitoring and audit will be performed by staff who are ICH/GCP trained and are competent in monitoring to GCP standards. A documented monitoring log and audit trail will be maintained throughout the lifetime of the study.

The Trial Manager in conjunction with the Clinical Trials Unit will oversee the set-up of and conduct of study procedures at each site. All source data, study documents, medical notes will be made available for Sponsor monitoring, and any external audits and inspections as appropriate, for example by the MHRA or Research Ethics Committee.

STUDY GOVERNANCE Trial Steering Committee (TSC):- TSC will comprise an independent chair, at least one other independent clinician with expertise in the management of diabetes, the chief investigator, key co-investigators, and representation from the Leicester Clinical Trials Unit. The study statisticians may attend as needed. This committee will be responsible for the overall management and oversight of the study and will meet once prior to start up and then every 6 months, normally within 2 months of the Data Safety Monitoring Committee (DSMC) (although additional meetings may be called by the Chief Investigator or TSC or DSMC chair) to review and approve protocol amendments and any sub-study proposals, review recruitment rates, protocol adherence, retention, compliance, safety issues, planned analyses and reports and act on recommendations of the DSMC. A copy of meeting minutes will be sent to the Sponsor.

Data Safety Monitoring Committee (DSMC):- DSMC will comprise an independent chair, independent clinician and independent statistician. The chief investigator or study statistician may be invited to attend to provide specific input by the DSMC Chair. The DSMC will be responsible for the interests and safety of the participants and its main role will be to make advisory recommendations to the TSC who will report to the Sponsor. To this end, the DSMC will undertake safety data reviews every six months after the first 5 participants are recruited unless otherwise deemed necessary. In addition, the DSMC will review analysis plans.

Project Management Committee (PMC):- PMC will report to the TSC and will include the chief investigator, other senior investigators and the day-to-day project management team. The group will meet monthly or bi-monthly depending on need, either face-to-face or by teleconference, to discuss the details and logistics of recruitment, retention and follow-up data collection.